Surgical approach for ground glass opacities

Introduction

Background

Since the introduction of low-dose computed tomography (CT) screening in high-risk individuals to reduce lung cancer mortality, there has been a sharp increase in the discovery of incidental pulmonary ground glass opacities (GGOs) (1). GGOs are focal areas of slightly increased attenuation on CT that do not obscure the underlying bronchial structures or pulmonary vessels. These entities present a clinical dilemma for both diagnosis and management. While GGOs can be present in benign conditions, such as fibrosis or inflammation, radiographically identical findings can also represent low-grade malignancy, such as adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and lepidic adenocarcinoma (2).

Rationale and knowledge gap

The natural history of GGOs is closely related to the proportion of solid component, size, and size progression over time (3,4). The management of GGOs is therefore categorized according to the number (solitary or multiple) and whether the nodules are pure GGOs or subsolid GGOs. In recent years, a number of guidelines have been published by the Fleischner Society, Japanese Society for CT Screening, National Comprehensive Cancer Network (NCCN), British Thoracic Society, American College of Chest Physicians (ACCP), and the American Association for Thoracic Surgery, all with similar themes but varying degrees of consensus on surveillance and threshold for invasive investigations or treatment. Emerging developments in surgical treatment have yet to be adequately incorporated into the existing guidelines for GGOs, as this entity presents unique challenges ranging from preoperative localization to the type of surgical resection.

Objective

The purpose of this narrative review is to present the most up-to-date evidence on GGO management for surgeons in order to illustrate the nuanced decision making based on numerous factors, including lesion characteristics, prognostic factors, surgical expertise and equipment availability.

Contemporary issues

Diagnostic dilemma

The first dilemma is when to intervene on a GGO. A GGO that disappears or decreases in size is presumed to be benign; however, there should be a high degree of suspicion for those that persistent for several months or show growth during surveillance (5,6). There is currently no consensus on when a GGO should undergo invasive investigation.

Ideally, correct tissue diagnosis guides surgery; however, diagnostic yields decrease with GGO size (80% for 16–20 mm, 50% for 11–15 mm, 35% for <10 mm) (7). Both transbronchial and transthoracic needle biopsy techniques have low sensitivity for pathologic confirmation of GGOs due to the small foci of invasive disease often being missed (8,9). As such, negative needle biopsy results lesions in GGOs clinically suspicious for malignancy should be treated as false negatives.

The prevalence of GGOs in the context of respiratory infection poses further diagnostic challenges in the post-coronavirus disease 2019 (COVID-19) era (10). A 2022 meta-analysis of 60 studies examining follow-up imaging within 12 months after inpatient admissions for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (the virus responsible for COVID-19), along with Middle East Respiratory Syndrome (MERS) and influenza pneumonia found GGO and consolidation in 56% of CT scans (11). Whether these are signs of ongoing inflammation, residual fibrosis, or slow growing lung cancers is unclear. At present, there is no consensus on the interval of follow up imaging or when to proceed with further diagnostic intervention for this patient population.

Role of positron emission tomography (PET)-CT in GGO diagnosis

The diagnostic value of fluorodeoxyglucose (FDG)-PET for GGO is still controversial. Although the NCCN guidelines (Lung Cancer Screening, Version 2.2024) supports FDG-PET/CT for incidental GGOs with solid components ≥6 mm, FDG-PET is neither specific nor sensitive for small pulmonary nodules, low cellular density lesions (i.e., GGO), and low-grade malignancies, such as AIS and carcinoid tumours. These types of cancers are frequently FDG-PET negative due to their low glucose metabolism, while inflammatory processes can be positive due to high glucose metabolism (12,13). Some studies have also suggested that benign GGOs present with higher FDG avidity on PET compared to malignant GGOs (14,15). Since subsolid GGO-predominant lung cancers rarely present with distant or lymph node metastasis, PET-CT has been believed to have little advantage in the staging for these patients.

Overview of current guidelines for surgical resection of GGO

The most recent Fleischner Society guidelines updated in 2017 recommend biopsy or resection for GGOs with suspicious morphology (i.e., lobulated margins or cystic components), a growing solid component (≥2 mm), or a solid component >8 mm (16). Although subsolid GGOs have a high risk of malignancy, lesions with a solid component <6 mm are typically low risk (i.e., AIS or MIA). Management decisions should be based on the most suspicious lesion in patients with multiple subsolid nodules; however, multiple suspicious nodules increase the overall risk of cancer, therefore surgical intervention should consider the potential for other nodules to grow and require treatment. It is important to note the Fleischner Society recommendations do not apply to lung cancer screening, patients younger than 35 years, and patients with a history of primary cancer or immunosuppression.

NCCN (Lung Cancer Screening guidelines, Version 2.2024) recommends biopsy or excision for subsolid lesions with a high suspicion for lung cancer on FDG-PET/CT (completed if the solid component is ≥6 mm). If lung cancer is confirmed, segmentectomy (preferred) or wedge resection is an acceptable alternative of lobectomy for (I) peripheral nodules ≤2 cm with pure AIS histology, (II) ≥50% ground-glass appearance on CT, or (III) long doubling time (≥400 days) during surveillance (NCCN NSCLC guidelines Version 4.2023).

The British Thoracic Society 2015 guidelines recommend surgical resection for GGOs that show growth or have morphological features suggestive of malignancy. The 3^rd edition of lung cancer management guidelines published in 2013 by the ACCP recommends biopsy or surgery for pure GGOs that grow or develop a solid component during surveillance. Biopsy and/or resection should also be considered if GGOs >10 mm remain persistent.

Localization of lesion

Video-assisted thoracoscopic surgery (VATS) is now routinely used for both diagnosis and treatment; it is the predominant surgical choice for solitary GGOs instead of the conventional thoracotomy. Finger palpation or visualization of the GGO is often difficult during VATS, necessitating preoperative localization. Various image-guided localization methods exist and are largely dictated by institutional practice and resource availability. These include both CT-guided percutaneous and transbronchial methods using wire, micro-coil, dye, lipiodol, radiotracer technetium (99mTc), and computer-assisted localization.

CT guided

• Hookwire: this is one of the most common localization tools that is safe and effective (12). There are no standardized criteria, but some proposed indications include: (I) GGO ≤20 mm; (II) nodules in the peripheral 1/3 of lung fields; and (III) GGO ≥5 mm from visceral pleura (17,18). Potential risks include pneumothorax, wire dislodgement, and intrapulmonary hematoma (19).
• Micro-coil: currently, this is likely the most versatile and ideal method of localization. Similar to the hookwire, micro-coil also increases the success rate of VATS excision of small peripheral pulmonary nodules. Indications include pure GGO and subsolid GGO with a solid portion ≤10 mm and >10 mm from the visceral pleura (20). Compared to the hookwire, micro-coils can be retained inside the body and does not require surgery to immediately follow localization. Compared to radionucleotide tags, micro-coil does not require special equipment or personnel training.
• Dye/contrast medium injection: methylene blue dye for lung nodule localization has been in use for almost three decades (21). There is little additional equipment cost aside from the existing CT-guided technical components, but the dye diffuses rapidly, requiring surgery to immediately follow localization. Anaphylaxis is a rare but well-known complication. Water-soluble contrast mediums, such as lipiodol, can be used instead. Lipiodol is retained up to 3 months after injection and has a limited area of diffusion in the lung parenchyma (22). Like barium, which is avoided as it can cause inflammatory changes affecting pathologic findings, lipiodol requires intraoperative fluoroscopic guidance to identify the marker. Many other mediums (e.g., India ink, indigo carmine, iopamidol) are available but less widely used for localization.

Virtual-assisted lung mapping (VAL-MAP)

For sub-lobar pulmonary resection, intraoperative identification of the lesion and defining the borders of resection are ongoing challenges. VAL-MAP is an effective tool that combines conventional flexible bronchoscopy with 3-dimensional (3D) virtual (CT) images to aid planning and injection of dye markers into the lung parenchyma (23). This process takes place prior to surgery where bronchoscopy is conducted via a preplanned route and dye is injected into multiple areas in the visceral pleura under fluoroscopic observation. A post-injection CT is required to confirm the injected locations to map them on 3D images. Intraoperatively, the injected locations are marked by blue spots on the lung surface.

VAL-MAP was originally conceived using indigo carmine as the dye of choice. In recent years, indocyanine green (ICG)—a dye most widely used in the near-infrared (NIR) fluorescence technique—has been demonstrated to have improved visibility on both CT and intraoperative findings compared to indigo carmine (24). Other non-dye markers have been proposed as well, including microcoils (25) and radiofrequency identification (RFID) tags. The RFID tag is similarly delivered via a flexible bronchoscope. A detector is able to determine the distance to each unique signal allowing accurate intraoperative detection of multiple RFID tags and triangulation of the lesion of interest (26).

Electromagnetic navigation bronchoscopy (ENB)

ENB uses flexible bronchoscopy combined with navigational platforms to access small peripheral tumours that are difficult to reach percutaneously or are invisible to conventional bronchoscopy. This technology uses an electromagnetic location board and thin-cut CT scans that are converted into a virtual 3D bronchoscopy reconstruction which allows a planned navigation route. Using this map, a flexible sensor probe is steered through the bronchial tree inside a working channel that can be extended to reach peripheral lesions. This allows real-time navigation to the peripheral lung nodules, facilitating biopsy and marker or dye placement. This allows VAL-MAP and surgery to be performed all at once in the operating room, thereby eliminating the need for post-injection CT prior to surgery. The superDimension™ Navigation System uses ENB in this manner. Similarly, the ILLUMISITE™ platform further corrects for the real-time discrepancy between a static CT scan and dynamic breathing lung to enhance visibility of the nodule. Robotic-assisted platforms, such as Ion™ and MONARCH™, that use articulating bronchoscopic tools to increase precise and diagnostic yield of biopsies are also available but not yet widely adopted.

Lobectomy, segmentectomy, or wedge resection

The extent of parenchymal resection is an important consideration, especially in patients without tissue diagnosis and those with multiple GGOs. The goal, as in any lung operation, is to reduce the volume of lung removed without compromising oncologic outcome. For the past 3 decades, lobectomy had been the standard of care for early non-small cell lung cancer (NSCLC) based on the 1995 randomized trial comparing lobectomy versus limited resection (27). Sublobar resection (segmentectomy and wedge resection) had been historically reserved for high-risk surgical candidates. Recently, however, new technologies with endobronchial ultrasound (EBUS), PET, and high-resolution CT have made the ideal operation for NSCLC tumours ≤2 cm become more controversial.

Defining the amount of GGO predominance by calculating the proportion of solid tumour in relation to overall tumour size—known as the consolidation-to-tumour ratio (CTR)—is a new variable that may provide further prognostic information to guide surgical decision making. Although CTR is not yet incorporated into NCCN, it is increasingly taken into account by studies of GGOs, particularly those published by the Japanese Clinical Oncology Group (JCOG). Specifically reporting on GGO-predominent lesions (i.e., CTR <0.5), several Japanese studies with long-term follow-up consistently reported excellent outcomes for patients undergoing sublobar resection without compromising survival or recurrence. For clinical stage IA (tumours ≤2 cm, American Joint Committee on Cancer 8^th edition) GGO-predominant adenocarcinomas (CTR <0.25) treated with sublobar resection, overall survival was >98% at 3 years (28,29) and 94% at 5 years (30). Disease-free survival at 5 years is as high as 99.7% (JCOG0804) (31). Ten-year sublobar resection outcomes for this group also appear to be excellent with 98.6% relapse-free survival and 98.5% overall survival (32). For solid-predominant lesions ≤2 cm (i.e., CTR >0.5), the JCOG0802 trial reported improved overall survival after segmentectomy but was associated with significantly higher local recurrence rate compared to lobectomy (33). For pure GGOs with adenocarcinoma, recently published 10-year follow-up reported no difference in recurrence-free survival between patients who underwent lobectomy versus sublobar resection (34).

There remains controversy in the choice of segmentectomy versus wedge resection for tumours ≤2 cm; some studies have suggested that long-term outcomes for GGOs between 1–2 cm after wedge resection are inferior to segmentectomy (35) while the two procedures are almost equivalent for tumours ≤1 cm. NCCN (Version 3.2023) prefers segmentectomy over wedge resection for GGO-predominant lesions ≤2 cm but does not provide strong evidence for this recommendation. Based on the totality of current evidence, wedge resection is likely sufficient for peripheral GGO-predominant lesions ≤2 cm where adequate margins (>2 cm) can be achieved, while segmentectomy should be considered for those deep within a certain lung segment or located between two segments.

For GGOs between 2–3 cm, there is currently little evidence besides the recently published JCOG1211 trial—a multi-centre, single-arm, confirmatory phase 3 trial evaluating the efficacy of segmentectomy for GGO-predominant lesions ≤3 cm. Given their excellent results for both overall and disease-free survival (98%), segmentectomy is recommended for GGO-predominant (CTR <0.5) lesions between 2–3 cm (36). It should be noted that while all margins achieved in the JCOG1211 trial were >2 cm, studies suggest that margin width does not seem to influence recurrence in GGO-predominant lesions, unlike in solid-predominant tumours (37). Lobectomy is required if the lesion is at the root segment of a bronchus, or if intraoperative biopsy demonstrates N1 disease. A surgical flowchart for GGOs ≤3 cm is illustrated in Figure 1.

Figure 1 Surgical flowchart for GGOs ≤3 cm. GGOs, ground glass opacities.

Role of ICG in segmentectomy

Precise identification of the intersegmental plane is an essential step in lung segmentectomy surgery. Traditionally, the inflation-deflation method was used, which involves clamping the responsible bronchus then inflating the remaining lung to identify the demarcation line. This technique, however, may not deliver satisfactory results due to ventilation into the desire segment through Kohn’s pores. Furthermore, the borders may shift once the lung is inflated and can obstruct the view, especially in VATS where the field of view is already limited. Since 2010 when Misaki et al. first reported on the use of ICG injections for segmental identification, there have been many studies supporting its usefulness in deflated lung with little variability. It can be given as a bronchial injection or more commonly given intravenously at 3–5 mg/kg (38). The drawbacks of this method include a short staining time (within minutes) and poor demarcation in patients with anthracosis (due to surface hypovascularity) or emphysema (39). Other innovative techniques include NIR fluorescence mapping with ICG, VAL-MAP, and selective segmental jet ventilation (40).

Lymph nodes dissection or sampling

While mediastinal lymph node dissection is standard in most resectable NSCLC, it is less clear for GGO-predominant lesions. Nodal metastasis has been reported, albeit rarely, in prior studies for both tumours containing <50% and >50% solid component (29,41,42); however, no hilar or mediastinal lymph node metastasis have been reported in GGO-predominant lesions (43,44). As such, many clinicians have chosen to perform selective lymph node sampling or forgo this part of GGO management altogether. The promising results of limited resection in GGO-predominant lesions suggest the biology of such tumours may not be the same as other traditional lung cancers, which require more extensive lymph node dissection. Certain risk factors independently associated with lymph node metastasis in patients with stage IA lung adenocarcinoma have been reported, which include solid-predominant nodules, elevated serum carcinoembryonic antigen (CEA) level, vascular tumour thrombus, and pleural invasion (43,45). In these select patients, mediastinal lymph node dissection should be performed. Ultimately, lymph node management in GGOs must await results from long-term survival data.

Multiple GGOs

Two or more GGOs discovered at the same time is an increasing trend among patients undergoing lung cancer screening, made diagnostically more complicated by the respiratory sequalae created by the COVID-19 pandemic. Surgical management of multiple GGOs, whether ipsilateral or bilateral, remains controversial as most clinicians consider multifocal GGOs to be primary lesions rather than intrapulmonary metastasis. There is no standardized algorithm for selecting which lesion to prioritize and what treatments to offer. Management largely relies on the lesions’ anatomical location, size, and number, as well as the surgeon’s judgement in the context of the patient’s pulmonary function and comorbidities.

It has been proposed that ipsilateral GGOs >10 mm and those with >50% solid component should be removed by single-stage surgical resection when possible. Formal lobectomy should be avoided for slow growing or multiple small GGOs that would require more than a sublobar resection due to their central location or multifocal nature; the main lesion and any easily accessible lesions should be removed with limited resection only. While simultaneous bilateral lung surgery is possible and has been successfully reported by Yao et al. (46), this method is likely not widely feasible. Two-stage VATS is preferred over synchronous resection to address GGOs in the contralateral chest (47). Surgery should be avoided if resection of multifocal GGOs would compromise postoperative respiratory function. Instead, these lesions should be considered for surveillance or stereotactic body radiation therapy.

Evidence suggests that management should be determined by one predominant lesion that carries the worst prognosis. Based on the Fleischner Society guidelines, if at least one of the GGOs ≥6 mm and persists on follow-up CT at 3–6 months, it is advised to consider multiple primary adenocarcinomas (16).

Conclusions

The management of GGOs is an evolving topic. There is a paucity of robust evidence to support many aspects of how GGOs are currently treated surgically, which must take into consideration various tumour characteristics, including size and degree of solid component within the lesion, as well as various patient factors that must be weighed to balance benefits of limited lung resection with the long-term risks to survival and recurrence. Overall, the term “ground glass opacities” likely represents a heterogeneous entity that is in many ways biologically distinct from traditional solid NSCLC and deserves further investigation with dedicated randomized trials to determine the best treatments going forward.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Donna E. Maziak and Patrick J. Villeneuve) for the series “Comprehensive Lung Cancer Care: A Continuum” published in Current Challenges in Thoracic Surgery. The article has undergone external peer review.

Peer Review File: Available at https://ccts.amegroups.org/article/view/10.21037/ccts-23-18/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://ccts.amegroups.org/article/view/10.21037/ccts-23-18/coif). The series “Comprehensive Lung Cancer Care: A Continuum” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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